1. Field of the Invention
This invention relates to quinoline derivatives, pharmaceutical compositions comprising them, and the use of such compounds in the treatment of central nervous system and peripheral diseases or disorders. This invention also relates to the use of such compounds in combination with one or more other CNS agents to potentiate the effects of the other CNS agents. The compounds of this invention are also useful as probes for the localization of cell surface receptors.
2. Description of the Related Art
The tachykinins represent a family of structurally related peptides originally isolated based upon their smooth muscle contractile and sialogogic activity. These mammalian peptides include substance P (SP), neurokinin A (NKA) and neurokinin xcex2 (NKB). Tachykinins are synthesized in the central nervous system (CNS), as well as in peripheral tissues, where they exert a variety of biological activities. Substance P can be produced from three different mRNAs (xcex1-, xcex2- and xcex3-preprotachykinin mRNAs) that arise from a single gene as a result of alternative RNA splicing, whereas NKA can be generated from either the xcex2- or the xcex3-preprotachykinin MRNA through posttranslationally processed precursor polypeptides. These precursors can also be differentially processed so that amino terminally extended forms of NKA (known as neuropeptide K and neuropeptide xcex3) are produced. NKB is produced from a separate mRNA arising from a second gene known as preprotachykinin B.
Three receptors for the tachykinin peptides have been moleculary characterized and are referred to as neurokinin-1 (NK-1), neurokinin-2 (NK-2) and neurokinin-3 (NK-3) receptors. The NK-1 receptor has a natural agonist potency profile of SP greater than NKA greater than NKB. The NK-2 receptor agonist potency profile is NKA greater than NKB greater than SP, and the NK-3 receptor agonist potency profile is NKB greater than NKA greater than SP. These receptors mediate the variety of tachykinin-stimulated biological effects that generally include 1) modulation of smooth muscle contractile activity, 2) transmission of (generally) excitatory neuronal signals in the CNS and periphery (e.g. pain signals), 3) modulation of immune and inflammatory responses, 4) induction of hypotensive effects via dilation of the peripheral vasculature, and 5) stimulation of endocrine and exocrine gland secretions. These receptors transduce intracellular signals via the activation of pertussis toxin-insensitive (Gxcex1q/11) G proteins, resulting in the generation of the intracellular second messengers inositol 1,4,5-trisphosyphate and diacylglycerol. NK-1 receptors are expressed in a wide variety of peripheral tissues and in the CNS. NK-2 receptors are expressed primarily in the periphery, while NK-3 receptors are primarily (but not exclusively) expressed in the CNS. Recent work confirms the presence of NK-3 receptor binding sites in the human brain.
Studies measuring the localization of NKB and NK-3 receptor mRNAs and proteins, along with studies performed using peptide agonists and non-peptide NK-3 receptor antagonists, provide a rationale for using NK-3 receptor antagonists in treating a variety of disorders in both the CNS and the periphery. In the CNS, activation of NK-3 receptors has been shown to modulate dopamine and serotonin release, indicating therapeutic utility in the treatment of a variety of disorders including anxiety, depression, schizophrenia and obesity. Further, studies in primate brain detect the presence of NK-3 MRNA in a variety of regions relevant to these disorders. With regard to obesity, it has also been shown that NK-3 receptors are located on MCH-containing neurons in the rat lateral hypothalamus and zona incerta. In the periphery, administration of NKB into the airways is known to induce mucus secretion and bronchoconstriction, indicating therapeutic utility for NK-3 receptor antagonists in the treatment of patients suffering from airway diseases such as asthma and chronic obstructive pulmonary disease (COPD). Localization of NK-3 receptors in the gastrointestinal (GI) tract and the bladder indicates therapeutic utility for NK-3 receptor antagonists in the treatment of GI and bladder disorders including inflammatory bowel disease and urinary incontinence.
Both peptide and nonpeptide antagonists have been developed for each of the tachykinin receptors. The first generation of peptide antagonists for the tachykinin receptors had problems with low potency, partial agonism, poor metabolic stability and toxicity, whereas the current generation of non-peptide antagonists display more drug-like properties. Unfortunately, previous non-peptide NK-3 receptor antagonists suffer from a number of problems such as species selectivity (which limits the potential to evaluate these compounds in many appropriate disease models). New non-peptide NK-3 receptor antagonists are therefore being sought, both as therapeutic agents and as tools to further investigate the anatomical and ultrastructural distribution of NK-3 receptors, as well as the physiologic and pathophysiologic consequences of NK-3 receptor activation.
The GABAA receptor superfamily represents one of the classes of receptors through which the major inhibitory neurotransmitter, xcex3-aminobutyric acid, or GABA, acts. Widely, although unequally, distributed through the mammalian brain, GABA mediates many of its actions through a complex of proteins called the GABAA receptor, which causes alteration in chloride conductance and membrane polarization.
A number of cDNAs for GABAA receptor subunits have been characterized. To date at least 6xcex1, 3xcex2, 3xcex3, 1xcex5, 1xcex4 and 2xcfx81 subunits have been identified. It is generally accepted that native GABAA receptors are typically composed of 2xcex1, 2xcex2, and 1xcex3 subunits (Pritchett and Seeburg Science 1989; 245:1389-1392 and Knight et. al., Recept. Channels 1998; 6:1-18). Evidence such as message distribution, genome localization and biochemical study results suggest that the major naturally occurring receptor combinations are xcex11xcex22xcex32, xcex12xcex23xcex32, xcex13xcex23xcex32, and xcex15xcex23xcex32, (Mohler et. al. Neuroch. Res. 1995; 20(5): 631-636).
Benzodiazepines exert their pharmacological actions by interacting with the benzodiazepine binding sites associated with the GABAA receptor. In addition to the benzodiazepine site, the GABAA receptor contains sites of interaction for several other classes of drugs. These include a steroid binding site, a picrotoxin site, and the barbiturate site. The benzodiazepine site of the GABAA receptor is a distinct site on the receptor complex that does not overlap with the site of interaction for GABA or for other classes of drugs that bind to the receptor (see, e.g., Cooper, et al., The Biochemical Basis of Neuropharmacology, 6th ed., 1991, pp. 145-148, Oxford University Press, New York). Early electrophysiological studies indicated that a major action of the benzodiazepines was enhancement of GABAergic inhibition. Compounds that selectively bind to the benzodiazepine site and enhance the ability of GABA to open GABAA receptor channels are agonists of GABA receptors. Other compounds that interact with the same site but negatively modulate the action of GABA are called inverse agonists. Compounds belonging to a third class bind selectively to the benzodiazepine site and yet have little or no effect on GABA activity, but can block the action of GABAA receptor agonists or inverse agonists that act at this site. These compounds are referred to as antagonists.
The important allosteric modulatory effects of drugs acting at the benzodiazepine site were recognized early and the distribution of activities at different receptor subtypes has been an area of intense pharmacological discovery. Agonists that act at the benzodiazepine site are known to exhibit anxiolytic, sedative, and hypnotic effects, while compounds that act as inverse agonists at this site elicit anxiogenic, cognition enhancing, and proconvulsant effects. While benzodiazepines have a long history of pharmaceutical use as anxiolytics, these compounds often exhibit a number of unwanted side effects. These may include cognitive impairment, sedation, ataxia, potentiation of ethanol effects, and a tendency for tolerance and drug dependence.
GABAA selective ligands may also act to potentiate the effects of various other CNS active compounds. For example, there is evidence that selective serotonin reuptake inhibitors (SSRIs) may show greater antidepressant activity when when used in combination with GABAA selective ligands than when used alone.
Disclosed are compounds, particulary quinoline derivatives that bind to cell surface receptors. Preferred compounds of the invention bind to neurokinin and/or GABA receptors, in particular these compounds possess affinity for NK-3 receptors and/or GABAA receptors. These compounds are therefore considered to be of potential use in the treatment of a broad array of diseases or disorders in patients which are characterized by modulation of NK-3 and/or GABAA receptors.
This invention provides compounds of general Formula I: 
or pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof, wherein in R1, R2, R3, R4, X, Y1 and Y2 are hereinafter defined.
Preferred compounds of this invention are ligands for neurokinin receptors and GABA receptors, especially NK-3 receptors and GABAA receptors, and are useful in the treatment of a wide range of diseases or disorders including, but not limited to depression, anxiety, sleep disorders, cognitive disorders, low alertness, psychosis, obesity, pain, Parkinson""s disease, Alzheimer""s disease, neurodegenerative diseases, movement disorders, Down""s syndrome, benzodiazepine overdoses, respiratory diseases, inflammatory diseases, neuropathy, immune disorders, migraine, biliary disfunction, and dermatitis.
The invention also provides pharmaceutical compositions comprising compounds of Formula I. The invention further comprises a method of treating a patient suffering from various central nervous system and peripheral diseases or disorders with an effective amount of a compound of the invention. Treatment of humans, domesticated companion animals (pets) or livestock animals suffering such conditions with an effective amount of a compound of the invention is contemplated by the invention.
Packaged pharmaceutical compositions including instructions for use of the composition are also included.
In a separate aspect, the invention provides a method of potentiating the actions of other CNS active compounds. This method comprises administering an effective amount of a compound of the invention with another CNS active compound.
The invention furthermore provides methods of using compounds of this invention as positive controls in assays for receptor activity and using appropriately labeled compounds of the invention as probes for the localization of receptors, particularly NK-3 and/or GABAA receptors, in tissue sections.
This invention relates to quinoline derivatives, pharmaceutical compositions comprising them, and the use of such compounds in the treatment of various central nervous system and peripheral diseases or disorders.
Accordingly, a broad embodiment of the invention is directed to compounds of Formula I: 
or pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof, wherein:
R1 is selected from:
hydrogen, halogen, hydroxy, C1-6 alkyl, xe2x80x94O(C1-6 alkyl), xe2x80x94NO2, xe2x80x94CN, xe2x80x94SO2NH2, xe2x80x94SO2NH(C1-6 alkyl), xe2x80x94SO2N (C1-6 alkyl)(C1-6 alkyl), amino, xe2x80x94NH(C1-6 alkyl), xe2x80x94N(C1-6 alkyl)(C1-6 alkyl), xe2x80x94N(C1-6 alkyl)CO(C1-6 alkyl), xe2x80x94N(C1-6 alkyl)CO2(C1-6 alkyl), xe2x80x94NHSO2(C1-6 alkyl), xe2x80x94N(C1-6 alkyl)SO2(C1-6 alkyl), xe2x80x94SO2NHCO(C1-6 alkyl), xe2x80x94CONHSO2(C1-6 alkyl), xe2x80x94CON(C1-6 alkyl)(C1-6 alkyl), xe2x80x94CO2(C1-6 alkyl), xe2x80x94S(C1-6 alkyl), xe2x80x94SO(C1-6 alkyl), or xe2x80x94SO2(C1-6 alkyl),
wherein said C1-6 alkyl may be straight, branched or cyclic, may contain one or two double or triple bonds, unsubstituted or substituted with one or more substituents selected from: hydroxy, oxo, fluoro, amino, C1-3 alkoxy;
R2 and R3 are independently selected from the groups consisting of:
(1) C1-8 alkyl, wherein said C1-8 alkyl is be straight, branched or cyclic, may contain one or two double or triple bonds, and is unsubstituted or substituted with one or more of the substituents selected from:
(i) hydroxy,
(ii) oxo,
(iii) fluoro,
(iv) amino,
(v) Ar1, wherein Ar1 is independently selected at each occurrence from phenyl, naphthyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazinyl, pyrimidyl, imidazolyl, benzoimidazolyl, furanyl, benzofuranyl, thiazolyl, benzothiazolyl, isothiazolyl, benzisothiazolyl, triazolyl, tetrazolyl, pyrazolyl, and benzopyrazolyl, each of which is unsubstituted or substituted with one or more substituents selected from:
hydrogen, halogen, hydroxy, C1-6 alkyl, xe2x80x94O(C1-6 alkyl), xe2x80x94NO2, xe2x80x94CN, xe2x80x94SO2NH2, xe2x80x94SO2NH(C1-6 alkyl), xe2x80x94SO2N(C1-6 alkyl)(C1-6 alkyl), amino, xe2x80x94NH(C1-6 alkyl), xe2x80x94N(C1-6 alkyl)(C1-6 alkyl), xe2x80x94N(C1-6 alkyl)CO(C1-6 alkyl), xe2x80x94N(C1-6 alkyl)CO2(C1-6 alkyl), xe2x80x94NHSO2(C1-6 alkyl), xe2x80x94N(C1-6 alkyl)SO2(C1-6 alkyl), xe2x80x94SO2NHCO(C1-6 alkyl), xe2x80x94CONHSO2(C1-6 alkyl), xe2x80x94CON(C1-6 alkyl)(C1-6 alkyl), xe2x80x94CO2(C1-6 alkyl), xe2x80x94S(C1-6 alkyl), xe2x80x94SO(C1-6 alkyl), or xe2x80x94SO2(C1-6 alkyl), wherein C1-6 alkyl, is defined as above,
(vi) xe2x80x94NR5R6, wherein R5 and R6 are independently selected at each occurrence from:
(a) hydrogen,
(b) C1-6 alkyl, wherein C1-6 alkyl is as defined above,
(c) xe2x80x94(CH2)nxe2x80x94Ar1, wherein n is 0, 1 or 2, and Ar1 is as defined above, or the groups R5 and R6 may be joined together to form a 4- to 8-membered ring of which the 4- to 8-membered ring may contain one or two double bonds, or one or two oxo, or one or two O, S or Nxe2x80x94R7 wherein R7 is independently selected at each occurrence from hydrogen, C1-6 alkyl, xe2x80x94(CH2)n-Ar1, wherein C1-6 alkyl, n and Ar1 are defined as above,
(vii) xe2x80x94OR5, wherein R5 is as defined above,
(viii) xe2x80x94CONR5R6 wherein R5 and R6 are as defined above,
(ix) xe2x80x94CO2R5, wherein said R5 is as defined above;
(2) Ar2, wherein Ar2 is independently selected at each occurrence from phenyl, naphthyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazinyl, pyrimidyl, imidazolyl, benzoimidazolyl, furanyl, benzofuranyl, thiazolyl, benzothiazolyl, isothiazolyl, benzisothiazolyl, triazolyl, tetrazolyl, pyrazolyl, or benzopyrazolyl, and unsubstituted or substituted with one or more substituents selected from:
hydrogen, halogen, hydroxy, C1-8 alkyl, xe2x80x94O(C1-8 alkyl), xe2x80x94NO2, xe2x80x94CN, xe2x80x94SO2NH2, xe2x80x94SO2NH(C1-8 alkyl), xe2x80x94SO2N(C1-8 alkyl)(C1-8 alkyl), amino, xe2x80x94NH(C1-8 alkyl), xe2x80x94N(C1-8 alkyl)(C1-8 alkyl), xe2x80x94N(C1-8 alkyl)CO(C1-8 alkyl), xe2x80x94N(C1-8 alkyl)CO2(C1-8 alkyl), xe2x80x94NHSO2(C1-8 alkyl), xe2x80x94N(C1-8 alkyl)SO2(C1-8 alkyl), xe2x80x94SO2NHCO(C1-8 alkyl), xe2x80x94CONHSO2(C1-8 alkyl), xe2x80x94CON(C1-8 alkyl)(C1-8 alkyl), xe2x80x94CO2(C1-8 alkyl), xe2x80x94S(C1-8 alkyl), xe2x80x94SO(C1-8 alkyl), or xe2x80x94SO2(C1-8 alkyl), wherein said C1-8 alkyl is as defined above;
(3) xe2x80x94NR8R9, wherein R8 and R9 are independently selected at each occurrence from:
(a) hydrogen,
(b) Ar2, wherein Ar2 is as defined above;
(c) C1-8 alkyl, wherein said C1-8 alkyl is as defined above;
xe2x80x83or the groups R8 and R9 may be joined together to form a 4- to 8-membered ring of which the 4- to 8-membered ring may contain one or more double bonds; one or more oxo; one or more O, S(O)n, Nxe2x80x94R7 wherein n and R7 are as defined above; one or more groups consisting of hydroxy, halogen, amino, C1-8 alkyl, xe2x80x94O(C1-8 alkyl), xe2x80x94NO2, xe2x80x94CN, xe2x80x94SO2NH2, xe2x80x94SO2NH(C1-8 alkyl), xe2x80x94SO2N(C1-8 alkyl)(C1-8 alkyl), amino, xe2x80x94NH(C1-8 alkyl), xe2x80x94N(C1-8 alkyl)(C1-8 alkyl), xe2x80x94N(C1-8 alkyl)CO(C1-8 alkyl), xe2x80x94N(C1-8 alkyl)CO2(C1-8 alkyl), xe2x80x94NHSO2(C1-8 alkyl), xe2x80x94N(C1-8 alkyl)SO2(C1-8 alkyl), xe2x80x94SO2NHCO(C1-8 alkyl), xe2x80x94CONHSO2(C1-8 alkyl), xe2x80x94CON(C1-8 alkyl)(C1-8 alkyl), xe2x80x94CO2(C1-8 alkyl), xe2x80x94S(C1-8 alkyl), xe2x80x94SO(C1-8 alkyl), or xe2x80x94SO2(C1-8 alkyl), wherein said C1-8 alkyl is as defined above;
(4) xe2x80x94OR8, wherein R8 is as defined above;
R4 is selected from:
hydrogen, halogen, hydroxy, C1-8 alkyl, xe2x80x94O(C1-8 alkyl), xe2x80x94NO2, xe2x80x94CN, xe2x80x94SO2NH2, xe2x80x94SO2NH(C1-8 alkyl), xe2x80x94SO2N(C1-8 alkyl)(C1-8 alkyl), amino, xe2x80x94NH(C1-8 alkyl), xe2x80x94N(C1-8 alkyl)(C1-8 alkyl), xe2x80x94N(C1-8 alkyl)CO(C1-8 alkyl), xe2x80x94N(C1-8 alkyl)CO2(C1-8 alkyl), xe2x80x94NHSO2(C1-8 alkyl), xe2x80x94N(C1-8 alkyl)SO2(C1-8 alkyl), xe2x80x94SO2NHCO(C1-8 alkyl), xe2x80x94CONHSO2(C1-8 alkyl), xe2x80x94CON(C1-8 alkyl)(C1-8 alkyl), xe2x80x94CO2(C1-8 alkyl), xe2x80x94S(C1-8 alkyl), xe2x80x94SO(C1-8 alkyl), xe2x80x94SO2(C1-8 alkyl), or Ar2 wherein Ar2 and said C1-8 alkyl are as defined above;
X is NH, O or Nxe2x80x94R10, wherein R10, is C1-8 alkyl, wherein said C1-8 alkyl is defined as above;
Y1 is xe2x80x94CR11R12xe2x80x94, xe2x80x94CR11R12(CH2)pxe2x80x94, xe2x80x94(CH2)pCR11R12xe2x80x94, or xe2x80x94(CH2)pCOxe2x80x94; where p is 0, 1, or 2; and R11 and R12 are independently selected at each occurrence from:
(1) hydrogen,
(2) Ar2, wherein Ar2 is as defined above;
(3) C1-8 alkyl wherein C1-8 alkyl is as defined above;
(4) xe2x80x94CONR8R9wherein R8 and R9 are as defined above,
(5) xe2x80x94CO2R8, wherein said R8 is as defined above; or the groups R11 and R12 may be joined together to form a monocyclic, bicyclic, or tricyclic ring;
Y2 is xe2x80x94CR11R12xe2x80x94 or xe2x80x94COxe2x80x94 with the proviso that Y2 is not xe2x80x94COxe2x80x94 when Y1 is xe2x80x94(CH2)pCOxe2x80x94, wherein p, R11 and R12 are as defined above; and
when X is Nxe2x80x94R10, the groups R10 and R11 may be joined to form a 5- to 8-membered ring which may contain one or more double bonds; one or more oxo; one or more O, S(O)n, Nxe2x80x94R7 wherein n and R7 are as defined above; one or more groups consisting of hydroxy, halogen, amino, C1-8 alkyl, xe2x80x94O(C1-8 alkyl), xe2x80x94NO2, xe2x80x94CN, xe2x80x94SO2NH2, xe2x80x94SO2NH(C1-8 alkyl), SO2N(C1-8 alkyl)(C1-8 alkyl), amino, xe2x80x94NH(C1-8 alkyl), xe2x80x94N(C1-8 alkyl)(C1-8 alkyl), xe2x80x94N(C1-8 alkyl)CO(C1-8 alkyl), xe2x80x94N(C1-8 alkyl)CO2(C1-8 alkyl), xe2x80x94NHSO2(C1-8 alkyl), xe2x80x94N(C1-8 alkyl)SO2(C1-8 alkyl), xe2x80x94SO2NHCO(C1-8 alkyl), xe2x80x94CONHSO2(C1 8 alkyl), xe2x80x94CON(C1-8 alkyl)(C1-8 alkyl), xe2x80x94CO2(C1-8 alkyl), xe2x80x94S(C1-8 alkyl), xe2x80x94SO(C1-8 alkyl), or xe2x80x94SO2(C1-8 alkyl) wherein said C1-8 alkyl is as defined above.
Preferred compounds include compounds of Formula I, and the pharmaceutically acceptable salts and solvates thereof, wherein X is NH or Nxe2x80x94R10, where R10 is as defined as for Formula I.
Other preferred compounds of general Formula I include compounds of Formula IA 
and the pharmaceutically acceptable salts and solvates thereof, wherein: R1, R2, R3, R4, R10, R11, and R12 are as defined as for Formula I.
More preferred compounds of general Formula I include compounds of Formula IB 
and the pharmaceutically acceptable salts and solvates thereof, wherein: R1 and R4 are as defined in Formula I;
Ra, Rb, and Rc and Rf, Rg, and Rh independently represent hydrogen, halogen, hydroxy, C1-6 alkyl, xe2x80x94O(C1-6 alkyl), xe2x80x94NO2, xe2x80x94CN, xe2x80x94SO2NH2, amino, xe2x80x94NH(C1-6 alkyl), xe2x80x94N(C1-6 alkyl)(C1-6 alkyl), xe2x80x94N(C1-6 alkyl)CO(C1-6 alkyl), xe2x80x94N(C1-6 alkyl)CO2(C1-6 alkyl), xe2x80x94CON(C1-6 alkyl)(C1-6 alkyl), xe2x80x94CO2(C1-6 alkyl;
Rd is hydrogen, straight or branched chain alkyl, or straight or branched chain alkoxy; and
R10 is hydrogen, methyl or ethyl.
Additional preferred compounds of general Formula I are compounds of Formula IC 
and the pharmaceutically acceptable salts and solvates thereof, wherein:
R1 and R4 are as defined in Formula I;
Ra, Rb, and Rc and Rf, Rg, and Rh independently represent hydrogen, halogen, hydroxy, C1-6 alkyl, xe2x80x94O(C1-6 alkyl), xe2x80x94NO2, xe2x80x94CN, xe2x80x94SO2NH2, amino, xe2x80x94NH(C1-6 alkyl), xe2x80x94N(C1-6 alkyl)(C1-6 alkyl), xe2x80x94N(C1-6 alkyl)CO(C1-6 alkyl), xe2x80x94N(C1-6 alkyl)CO2(C1-6 alkyl), xe2x80x94CON(C1-6 alkyl)(C1-6 alkyl), xe2x80x94CO2(C1-6 alkyl);
Rd is hydrogen or straight or branched chain alkyl or straight or branched chain alkoxy;
R4 is as defined in Formula I and
R10 is hydrogen, methyl or ethyl.
Still other preferred compounds of general Formula I include compounds of Formula ID 
and the pharmaceutically acceptable salts and solvates thereof, wherein:
Ra, Rb, and Rc independently represent hydrogen, halogen, hydroxy, C1-6 alkyl, xe2x80x94O(C1-6 alkyl), xe2x80x94NO2, xe2x80x94CN, xe2x80x94SO2NH2, amino, xe2x80x94NH(C1-6 alkyl), xe2x80x94N(C1-6 alkyl)(C1-6 alkyl), xe2x80x94N(C1-6 alkyl)CO(C1-6 alkyl), xe2x80x94N(C1-6 alkyl)CO2(C1-6 alkyl), xe2x80x94CON(C1-6 alkyl)(C1-6 alkyl), xe2x80x94CO2(C1-6 alkyl), wherein C1-6alkyl is as defined above;
R4 is as defined for Formula I;
R10 is hydrogen, methyl or ethyl; and
R11 and R12 are joined together to form a monocyclic, bicyclic, or tricyclic ring.
Yet other preferred compounds of general Formula I include compounds of Formula IE 
and the pharmaceutically acceptable salts and solvates thereof, wherein:
Ra, Rb, and Rc and Rf, Rg, and Rh independently represent hydrogen, halogen, hydroxy, C1-6 alkyl, xe2x80x94O(C1-6 alkyl), xe2x80x94NO2, xe2x80x94CN, xe2x80x94SO2NH2, amino, xe2x80x94NH(C1-6 alkyl), xe2x80x94N(C1-6 alkyl)(C1-6 alkyl), xe2x80x94N(C1-6 alkyl)CO(C1-6 alkyl), xe2x80x94N(C1-6 alkyl)CO2(C1-6 alkyl), xe2x80x94CON(C1-6 alkyl)(C1-6 alkyl), xe2x80x94CO2(C1-6 alkyl);
R4 is as defined for Formula I; and
Rd and R10 together form an alkylene group of from 3-5 carbon atoms each of which is optionally substituted with methyl or ethyl.
Another class of preferred compounds of general Formula I includes compounds of Formula IF 
and the pharmaceutically acceptable salts and solvates thereof, wherein:
Ra, Rb, and Rc independently represent hydrogen, halogen, hydroxy, C1-6 alkyl, xe2x80x94O(C1-6 alkyl), xe2x80x94NO2, xe2x80x94CN, xe2x80x94SO2NH2, amino, xe2x80x94NH(C1-6 alkyl), xe2x80x94N(C1-6 alkyl)(C1-6 alkyl), xe2x80x94N(C1-6 alkyl)CO(C1-6 alkyl), xe2x80x94N(C1-6 alkyl)CO2(C1-6 alkyl), xe2x80x94CON(C1-6 alkyl)(C1-6 alkyl), xe2x80x94CO2(C1-6 alkyl), wherein C1-6alkyl is as defined above;
R1, R2, and R4 are as defined in Claim 1;
R10 is hydrogen, methyl or ethyl; and
R11 and R12 are independently from:
(1) hydrogen,
(2) Ar2,
(3) xe2x80x94C1-8 alkyl,
(4) xe2x80x94CONR8R9 wherein R8 and R9 are as defined in Claim 1, and
(5) xe2x80x94CO2R8, wherein said R8 is as defined in Claim 1.
Particularly preferred compounds of Formula IF are compounds of Formula IG 
and the pharmaceutically acceptable salts and solvates thereof, wherein:
Ra, Rb, and Rc and Rf, Rg, and Rh independently represent hydrogen, halogen, hydroxy, C1-6 alkyl, xe2x80x94O(C1-6 alkyl), xe2x80x94NO2, xe2x80x94CN, xe2x80x94SO2NH2, amino, xe2x80x94NH(C1-6 alkyl), xe2x80x94N(C1-6 alkyl)(C1-6 alkyl), xe2x80x94N(C1-6 alkyl)CO(C1-6 alkyl), xe2x80x94N(C1-6 alkyl)CO2(C1-6 alkyl), xe2x80x94CON(C1-6 alkyl)(C1-6 alkyl), xe2x80x94CO2(C1-6 alkyl);
Rd is hydrogen or straight or branched chain alkyl or straight or branched chain alkoxy;
R1 and R4 are as defined for Formula I; and
R10 is hydrogen, methyl or ethyl.
Also, preferred compounds of the invention include compounds of general Formula IA wherein X is oxygen. These compounds will be referred to as compounds of Formula IH.
More preferred compounds of Formula IH are compounds of Formula Ii 
and the pharmaceutically acceptable salts and solvates thereof, wherein:
R1, R2, R4, R11, and R12 are as defined for Formula I; and Ra, Rb, and Rc independently represent hydrogen, halogen, hydroxy, C1-6 alkyl, xe2x80x94O(C1-6 alkyl), xe2x80x94NO2, xe2x80x94CN, xe2x80x94SO2NH2, amino, xe2x80x94NH(C1-6 alkyl), xe2x80x94N(C1-6 alkyl)(C1-6 alkyl), xe2x80x94N(C1-6 alkyl)CO(C1-6 alkyl), xe2x80x94N(C1-6 alkyl)CO2(C1-6 alkyl), xe2x80x94CON(C1-6alkyl)(C1-6 alkyl), xe2x80x94CO2(C1-6 alkyl).
Particularly preferred compounds of Formula IH are compounds of Formula IJ 
and the pharmaceutically acceptable salts and solvates thereof, wherein:
R1 and R4 are as defined for Formula I;
Ra, Rb, and Rc and Rf, Rg, and Rh independently represent hydrogen, halogen, hydroxy, C1-6 alkyl, xe2x80x94O(C1-6 alkyl), xe2x80x94NO2, xe2x80x94CN, xe2x80x94SO2NH2, amino, xe2x80x94NH(C1-6 alkyl), xe2x80x94N(C1-6 alkyl)(C1-6 alkyl), xe2x80x94N(C1-6 alkyl)CO(C1-6 alkyl), xe2x80x94N(C1-6 alkyl)CO2(C1-6 alkyl), xe2x80x94CON(C1-6 alkyl)(C1-6 alkyl), xe2x80x94CO2(C1-6 alkyl); and
Rd is hydrogen or straight or branched chain alkyl or straight or branched chain alkoxy.
In certain instances, the compounds of the present invention have asymmetric centers and this invention includes all of the optical isomers and mixtures thereof.
In addition compounds with carbon-carbon double bonds may occur in Zxe2x80x94 and Exe2x80x94 forms with all isomeric forms of the compounds being included in the present invention.
When any variable (e.g. alkyl, Ar1, Ar2, R5, R6, R8, R9, R11, R12, etc.) occurs more than one time in Formula I, its definition on each occurrence is independent of its definition at every other occurrence.
As used herein, the term xe2x80x9calkylxe2x80x9d includes straight or branched chain alkyl groups and cycloalkyl groups that also may contain double or triple bonds. Examples of xe2x80x9calkylxe2x80x9d include methyl, ethyl, propyl, isopropyl, butyl, iso-, sec- and tert-butyl, pentyl, hexyl, heptyl, 3-ethylbutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and the like. Where the number of carbon atoms is designed at the alkyl group includes that number of carbon atoms. When reference is made herein to C1-6 alkyl which it may contain one or two double or triple bond it is understood that at least two carbons are present in the alkyl for one double or triple bond, and at least four carbons for two double or triple bonds. The term xe2x80x9calkoxyxe2x80x9d represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge, such as methoxy, ethoxy, propoxy and isopropoxy.
By the term xe2x80x9chalogenxe2x80x9d is meant fluorine, chlorine, bromine, and iodine.
The term xe2x80x9cmonocyclicxe2x80x9d includes, but is not limited to cyclopentyl, cyclohexyl or cycloheptyl; xe2x80x9cbicyclicxe2x80x9d includes, but is not limited to indanyl, tetrahydronaphthyl, chromanyl benzo[a][7]annulenyl, bicyclo[4.4.0]decanyl, bicyclo[4,3.0]nonanyl, bicyclo[3.3.0]octanyl; xe2x80x9ctricyclicxe2x80x9d includes, but is not limited to dibenzoannulenyl, dibenzoxepanyl, dibezothiepanyl.
As used herein, the terms xe2x80x9cpatientsxe2x80x9d refers to humans as well as other mammals including pets such as dogs and cats and livestock such as cattle and sheep.
This invention also includes methods for using compounds of Formula I to treat diseases or disorders in patients in which mediation by NK-3 receptors and/or GABAA receptors is of importance.
Preferred compounds of this invention are ligands for neurokinin and GABA receptors, in particular NK-3 receptors and/or GABAA receptors, and are useful in the treatment of a wide range of diseases or disorders of the central nervous system (CNS) and periphery in mammals in which modulation of NK-3 receptors and/or GABAA receptors is of importance. These include depression, anxiety, panic disorder, obsessive compulsive disorder, psychosis and schizophrenia, sleep disorders, cognitive disorders, low alertness, psychosis and schizophrenia, neurodegenerative disorders such as dementia, Alzheimer""s diseases, Parkinson""s disease, Huntington""s disease, Down""s syndrome, benzodiazepine overdoses, stress related somatic disorders, reflex sympathetic dystrophy, dysthmic disorders, obesity, eating disorders, drug and alcohol addiction, movement disorders, convulsive disorders such as epilepsy, migraine, headache, multiple sclerosis and other demyelinating diseases, AIDS related neuropathy, chemotherapy-induced neuropathy and neuralgia, diabetic or peripheral neuropathy, neurogenic inflammation, inflammatory pain, neuropathic pain, and other types of chronic or acute pain, Reynaud""s disease, vasodilation, vasospasm, angina, asthma, chronic obstructive pulmonary diseases, airway hyperreactivity, cough, allergic rhinitis, bronchospasm, bronchopneumonia, ocular inflammation, inflammatory bowel disease, Crohn""s disease, ulcerative colitis, biliary disfunction, skin disorders and itch, hypersensitivity disorders, atopic dermatitis, contact dermatitis, cutaneous wheal and flare, renal disorders, urinary incontinence, immune system disorders and adverse immunological reactions, fibrositis, osteoarthritis, eosinophilic fascioliasis, and scleroderma. Compounds contained in the invention are also useful for the diagnosis of disorders involving mediation by neurokinin NK-3 receptors and/or GABAA receptors in patients.
Non-toxic pharmaceutical salts include salts, include, but not limited to salts with inorganic acids such as hydrochloride, sulfate, phosphate, diphosphate, hydrobromide, and nitrite or salts with an organic acid such as malate, maleate, fumarate, tartrate, succinate, citrate, acetate, lactate, methanesulfonate, p-toluenesulfonate, 2-hydroxyethylsulfonate, pamoate, salicylate and stearate. Similarly, pahrmaceutically acceptable cations include, but are not limited to sodium, potassium, calcium, aluminum, lithium and ammonium.
The present invention also encompasses the prodrugs of the compounds of Formula I. Those skilled in the art will recognize various synthetic methodologies (references by N. Bodor, Drugs of the Future, 1981, 6, 165-182, or H. Bundgaard, Advanced Drug Delivery Reviews, 1989, 3, 39-65) which may be employed to prepare non-toxic pharmaceutically acceptable prodrugs of the compounds encompassed by Formula I.
The compounds of general Formula I may be administered orally, topically, parenterally, by inhalation or spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques. In addition, there is provided a pharmaceutical formulation comprising a compound of general Formula I and a pharmaceutically acceptable carrier. One or more compounds of general Formula I may be present in association with one or more non-toxic pharmaceutically acceptable carriers and/or diluents and/or adjuvants and if desired other active ingredients. The pharmaceutical compositions containing compounds of general Formula I may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs.
Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monosterate or glyceryl distearate may be employed.
Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
Oily suspensions may be formulated by suspending the active ingredients in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide palatable oral preparations. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
Pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides, for example sorbitan monoleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monoleate. The emulsions may also contain sweetening and flavoring agents.
Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be sterile injectable solution or suspension in a non-toxic parentally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer""s solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
The compounds of general Formula I may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.
Compounds of general Formula I may be administered parenterally in a sterile medium. The drug, depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle. Advantageously, adjuvants such as local anesthetics, preservatives and buffering agents can be dissolved in the vehicle.
Dosage levels of the order of from about 0.1 mg to about 140 mg per kilogram of body weight per day are useful in the treatment of the above-indicated conditions (about 0.5 mg to about 7 g per patient per day). The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Dosage unit forms will generally contain between from about 1 mg to about 500 mg of an active ingredient.
Frequency of dosage may also vary depending on the compound used and the particular disease treated. However, for treatment of most disorders, a dosage regimen of 4 times daily or less is preferred. For the treatment of schizophrenia, depression, cognitive deficity or anxiety a dosage regimen of 1 or 2 times daily is particularly preferred. For the treatment of sleep disorders a single dose that rapidly reaches effective concentrations is desirable.
It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
Preferred compounds of the invention will have certain pharmacological properties. Such properties include, but are not limited to oral bioavailability, low toxicity, low serum protein binding and desirable in vitro and in vivo half-lifes. Penetration of the blood brain barrier for compounds used to treat CNS disorders is necessary, while low brain levels of compounds used to treat periphereal disorders are often preferred.
Assays may be used to predict these desirable pharmacological properties. Assays used to predict bioavailability include transport across human intestinal cell monolayers, including Caco-2 cell monolayers. Toxicity to cultured hepatocyctes may be used to predict compound toxicity. Penetration of the blood brain barrier of a compound in humans may be predicted from the brain levels of the compound in laboratory animals given the compound intravenously.
Serum protein binding may be predicted from albumin binding assays. Such assays are described in a review by Oravcovxc3xa1, et al. (Journal of Chromatography B (1996) volume 677, pages 1-27).
Compound half-life is inversely proportional to the frequency of dosage of a compound. In vitro half-lifes of compounds may be predicted from assays of microsomal half-life as described by Kuhnz and Gieschen (Drug Metabolism and Disposition, (1998) volume 26, pages 1120-1127).
The present invention also pertains to packaged pharmaceutical compositions for treating disorders responsive to NK-3 and/or GABAA receptor modulation, e.g., treatment schizoprenia, depression, or chronic pulmonary obstructive disorder by NK-3 receptor modulation or treatment of sleep disorders, cognitive deficits, anxiety or depression by GABA, receptor modulation. The packaged pharmaceutical compositions include a container holding a therapeutically effective amount of at least one NK-3 and/or GABAA receptor modulator as described supra and instructions (e.g., labeling) indicating the the contained NK-3 and/or GABAA receptor ligand is to be used for treating a disorder responsive to NK-3 and/or GABAA receptor modulation in the patient.
The present invention also pertains to methods of inhibiting the binding of neurokinin to the NK-3 receptor which methods involve contacting a compound of the invention with cells expressing NK-3 receptors, wherein the compound is present at a concentration sufficient to inhibit neurokinin binding to cells expressing a cloned human NK-3 receptor in vitro and to method for altering the signal-tranducing activity of NK-3 receptors, said method comprising exposing cells expressing such receptor to an effective amount of a compound of the invention.
Preferred compounds of the invention show selectivity for the NK-3 Receptor or the GABAA receptor as measured by standard assays for NK-3 and GABAA Receptor binding (See example 41 for a standard assay of NK-3 receptor binding and example 43 for a standard assay of GABAA receptor binding).
Preferred compounds of the invention are those that show selectivity for the NK-3 receptor over the GABAA receptor and exhibit a 10-fold greater affinity for the NK-3 receptor; more preferred compounds exhibit a 100-fold greater affinity for the NK-3 receptor; and most preferred compounds exhibit a 1000-fold greater affinity for the NK-3 receptor in a standard assay of NK-3 receptor binding than for the GABAA receptor in a standard assay of GABAA receptor binding.
Preferred compounds of the invention are those that show selectivity for the GABAA receptor over the NK-3 receptor and exhibit a 10-fold greater affinity for the GABAA receptor, more preferred compounds exhibit a 100-fold greater affinity for the GABAA receptor, and most preferred compounds exhibit a 1000-fold greater affinity for the GABAA receptor in a standard assay of GABAA receptor binding than for the NK-3 receptor in a standard assay of Nk-3 receptor binding.
Several methods for preparing the compounds of this invention are illustrated in the following Scheme I, II and III. The synthesis of compounds of Formula II is described in detail in the several publications including Giardina et. al. J. Med. Chem. 1997, 40, 1794-1807 and Giardina et. al. J. Heterocyclic Chem., 1997, 34, 557-559 and references cited therein. It will be recognized by those skilled in the art that the structures of Formula III, IV, and V can be readily synthesized from various readily available amino acids. Alternatively, various readily available ketones and aldeydes can be converted to the corresponding aminocyanides and cyanohydrins and subsequently reduced to the desired diamines and aminoalcohols. Those skilled in the art will recognize that in certain instances it will be necessary to utilize compounds of Formula II and Formula III bearing protecting groups and that these groups can be removed in a subsequent reaction to yield compounds of Formula I as described in xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d, 2nd Ed., Greene, T. W. and related publications. 
wherein R1, R2, R3, R4, R10, R11, and R12 are as defined above, W is xe2x80x94CO2H, xe2x80x94CO2Me, xe2x80x94CO2Et, xe2x80x94C(OEt)3, xe2x80x94Cxe2x95x90NHOMe, xe2x80x94Cxe2x95x90NHOEt, xe2x80x94CSNH2, xe2x80x94Cxe2x95x90NHNH2, or xe2x80x94CN.
Condition A includes, but is not limited to, heating with or without a solvent such as toluene, ethanol, or xylene at 40-250xc2x0 C.; heating with AlMe3 in a solvent such as toluene at 80-120xc2x0 C. and, ocassionally, continued heating in the presence of Lawesson""s reagent; or stirring at room temperature in presence of triphenylphosphine, CCl4 and a base such as triethylamine or diisoprpylethylamine in a solvent such as acetonitrile or a mixture of solvents such as acetonitrile-pyridine. 
wherein R1, R2, R3, R4, R10, R11, and R12 are as defined above, W is xe2x80x94COCl or xe2x80x94CO2H.
Condition B includes, but is not limited to, reaction of the amine with acid chloride (Wxe2x95x90COCl) in the presence of base as well as amide bond forming conditions such as those employing the BOP reagent in the presence of base.
Condition C includes, but is not limited to, treatment with sodium methoxide in the presence of methanol as solvent. 
wherein R1, R2, R3, R4, R11, R12 are as defined above, W is xe2x80x94CO2H, xe2x80x94CO2Me, xe2x80x94CO2Et, xe2x80x94C(OEt)3, xe2x80x94Cxe2x95x90NHOMe, xe2x80x94Cxe2x95x90NHOEt, xe2x80x94CSNH2, or xe2x80x94Cxe2x95x90NHNH2.
Condition A includes, but is not limited to, heating with or without a solvent such as toluene, ethanol, or xylene at 40-250xc2x0 C.; heating with AlMe3 in a solvent such as toluene at 80-120xc2x0 C. and, ocassionally, continued heating in the presence of Lawesson""s reagent; or stirring at room temperature in presence of triphenylphosphine, CCl4 and a base such as triethylamine or diisoprpylethylamine in a solvent such as acetonitrile or a mixture of solvents such as acetonitrile-pyridine.
Those having skill in the art will recognize that the starting materials may be varied and additional steps employed to produce compounds encompassed by the present invention, as demonstrated by the following examples. In some cases protection of certain reactive functionalities may be necessary to achieve some of the above transformations. In general the need for such protecting groups will be obvious to those skilled in the art of organic synthesis as well as the conditions necessary to attach and remove such groups.